Methods for preparing 5- and 6-benzyl-functionalized quinoxalines

ABSTRACT

The present invention pertains to methods for preparing 5- and 6-benzyl functionalized quinoxalines. In a first embodiment, the method comprises contacting an aqueous suspension of a 5- and 6-halomethyl quinoxaline with a water-soluble nucleophile. In a second embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline with an organic solvent-soluble nucleophile in an inert polar organic solvent. In a third embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline in an organic solvent with an aqueous solution of a water-soluble nucleophile in the presence of a phase transfer catalyst.

This application is a division of U.S. application Ser. No. 09/909,002,filed on 19 Jul. 2001 now U.S. Pat. No. 6,548,670.

BACKGROUND OF THE INVENTION

The present invention relates to a method for preparing 5- and 6-benzylfunctionalized quinoxalines.

The disclosures referred to herein to illustrate the background of theinvention and to provide additional detail with respect to its practiceare incorporated herein by reference and, for convenience, arenumerically referenced in the following text and respectively grouped inthe appended bibliography.

Substituted quinoxalines are important chemical intermediates for thepreparation of pharmaceutical compounds, such as AMPHAKINE CX516 ®[1-(quinoxalin-6-ylcarbonyl) piperidine]. Substituted quinoxalines aretypically prepared by condensation of substituted ortho-diaminobenzeneswith sodium glyoxal bisulfite as set out below (1):

For example, 7-methoxy-5-aminoquinoxaline has been prepared bycondensation of 3,4,5-triaminoanisole with sodium glyoxal bisulfite (2):

Similarly, 7-methoxy-5-aminoquinoxaline and7-methoxy-5-hydroxyamino-quinoxaline have been prepared from3,5-dinitro-4-aminoanisole, which in turn was prepared by nitration ofm-nitrobenzenesulfonyl-p-aminoanisole (3).

Nevertheless, there are no reported procedures for preparing6-hydroxymethylquinoxaline by condensation of3,4-diaminohydroxymethylbenzene with sodium glyoxal bisulfite,presumably because such a method is not trivial and requires multiplesteps. Because attempts to prepare 5- and 6-benzyl functionalizedquinoxalines via a one-step selective reaction of the benzyl group werenot successful, a two-step method to prepare 5- and 6-benzylfunctionalized quinoxalines was developed.

BRIEF SUMMARY OF THE INVENTION

In a first embodiment, the present invention pertains to a method forpreparing a compound having Formula (I).

In this first embodiment, the method comprises contacting an aqueoussuspension of a compound having Formula (II) with a water-solublenucleophile, N¹, containing moiety Y; wherein X is chloro or bromo; R₁is selected from the group consisting of hydrogen and branched andunbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y isselected from the group consisting of —OR₂, —NHR₂, —NR₂R₃, —SR₂, and—CN; and R₂ and R₃ are independently selected from the group consistingof hydrogen and branched and unbranched alkyl groups having from 1 to 4carbon atoms.

In a second embodiment, the present invention pertains to a method forpreparing a compound having Formula (I).

In this second embodiment, the method comprises contacting a compoundhaving Formula (II) with an organic solvent-soluble nucleophile, N²,containing moiety Y, in an inert polar organic solvent; wherein X ischloro or bromo; R₁ is selected from the group consisting of hydrogenand branched and unbranched alkyl and aryl groups having from 1 to 9carbon atoms; Y is selected from the group consisting of —OR₂, —NHR₂,—NR₂R₃, and —SR₂; and R₂ and R₃ are independently selected from thegroup consisting of hydrogen and branched and unbranched alkyl and arylgroups having from 5 to 9 carbon atoms.

In a third embodiment, the present invention pertains to a method forpreparing a compound having Formula (I).

In this third embodiment, the method comprises contacting a compoundhaving Formula (II) in an organic solvent with an aqueous solution of awater-soluble nucleophile, N¹, containing moiety Y, in the presence of aphase transfer catalyst; wherein X is chloro or bromo; R₁ is selectedfrom the group consisting of hydrogen and branched and unbranched alkyland aryl groups having from 1 to 9 carbon atoms; Y is selected from thegroup consisting of —OR₂, —NHR₂, —NR₂R₃, —SR₂, and —CN; and R₂ and R₃are independently selected from the group consisting of hydrogen andbranched and unbranched alkyl groups having from 1 to 4 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

The present invention pertains to methods for preparing 5- and 6-benzylfunctionalized quinoxalines. In a first embodiment, the method comprisescontacting an aqueous suspension of a 5- and 6-halomethyl quinoxalinewith a water-soluble nucleophile. In a second embodiment, the methodcomprises contacting a 5- and 6-halomethyl quinoxaline with an organicsolvent-soluble nucleophile in an inert polar organic solvent. In athird embodiment, the method comprises contacting a 5- and 6-halomethylquinoxaline in an organic solvent with an aqueous solution of awater-soluble nucleophile in the presence of a phase transfer catalyst.

The 5- and 6-halomethyl quinoxalines may be prepared from 5- and6-methyl quinoxalines, which in turn may be prepared fromortho-diaminotoluenes, such as 2,3- and 3,4-diaminotoluene, bycondensation with sodium glyoxal bisulfite. The preparation ofortho-diaminotoluenes is not trivial because the nitration of tolueneyields mainly 2,4-dinitrotoluene, the precursor of 2,4-diaminotoluene(TDA, toluene-diamine), and only 4% or less of the ortho-isomers.However, 2,4-diaminotoluene is a bulk chemical, from which theortho-diamine isomers are removed by distillation, and consequently usesfor the ortho-diamine by-products are desired. The present inventionprovides a simple route to compounds such as 6-hydroxymethyl-quinoxalineby taking advantage of the availability of ortho-toluene diamine (OTD)using selective functionalization of the methyl group without affectingthe aromatic rings.

Because attempts to prepare 5- and 6-benzyl functionalized quinoxalinesvia a one-step selective reaction of the benzyl group were notsuccessful, a two-step method to prepare 5- and 6-benzyl functionalizedquinoxalines was developed.

In the first step, a 5- or 6-benzyl-quinoxaline is halogenated toprovide the corresponding 5- or 6-halomethyl-quinoxaline intermediate.

X is halogen. The term “halogen”, as used herein, refers to fluorine,chlorine, bromine, and iodine. Preferred halogens are chlorine andbromine.

In the first step of the synthesis, a benzylic methyl heterocycliccompound and a halogenating agent, such as N-chlorosuccinimide (NCS) orN-bromosuccinimide (NBS), are reacted in the presence of a radicalinitiator, such as benzoyl peroxide or azobisisobutyronitrile, in asuitable solvent, to form the respective 5- or 6-halomethyl quinoxaline(I). Suitable solvents may be selected from the group consisting offluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene,dichlorobenzenes, trichlorobenzenes, α,α,α-trifluorotoluene andα,α,α-trichlorotoluene. The method typically affords good yields ofhalomethyl-quinoxalines when [6QX]/[benzoyl peroxide]≦40 whilemaintaining a temperature in the range of 60° C. to 115° C. for a periodof 1 to 12 hours. Yields for benzylic brominations (conversions ≧95%,selectivities ≧97%) are in general better than for benzylicchlorinations (conversions 60%, selectivities ˜75-80%). The 5- or6-halomethyl quinoxaline may be a 5-halomethyl quinoxaline or may be a6-halomethyl quinoxaline. The halomethyl may be a chloromethyl or may bea bromomethyl.

This first step is more fully described in a copending patentapplication entitled “Method For Preparing Halomethyl HeterocyclicCompounds” filed by applicant concurrently with the present patentapplication and assigned to the assignee of this application, which ishereby incorporated by reference.

In the second step, the 5- or 6-halomethyl-quinoxaline intermediate (II)is contacted with a nucleophile to yield the corresponding 5- or6-benzyl functionalized quinoxaline (I).

In a first embodiment, the present invention pertains to a method forpreparing a compound having Formula (I) which comprises contacting anaqueous suspension of a compound having Formula (II) with awater-soluble nucleophile, N¹, containing moiety Y.

In this first embodiment, the compound having Formula (I) may be:

R₁ may be selected from the group consisting of hydrogen and branchedand unbranched alkyl and aryl groups having from 1 to 9 carbon atoms.Preferably, R₁ is selected from the group consisting of hydrogen andbranched and unbranched alkyl and aryl groups having from 1 to 6 carbonatoms, more preferably R₁ is selected from the group consisting ofhydrogen and branched and unbranched alkyl groups having from 1 to 3carbon atoms, and most preferably R₁ is hydrogen.

The water-soluble nucleophiles, N¹, containing moiety Y, which may beemployed in the present invention may be any water-soluble nucleophilewhich is capable of selectively displacing the halogen group attached tothe benzylic position of the heterocyclic compound in an aqueoussuspension. The term “water-soluble nucleophile”, as used herein, refersto a nucleophile that can be dissolved in water to yield a solution witha molarity equal to, or greater than, 0.01. Non-limiting illustrativewater-soluble nucleophiles are those that contain a Y moiety, where Ymay be selected from the group consisting of —OR₂, —NHR₂, —NR₂R₃, —SR₂,and —CN. R₂ and R₃ are independently selected from the group consistingof hydrogen and branched and unbranched alkyl groups having from 1 to 4carbon atoms. Preferably, R₂ and R₃ are independently selected from thegroup consisting of hydrogen and branched and unbranched alkyl groupshaving from 1 to 3 carbon atoms, more preferably R₂ and R₃ areindependently selected from the group consisting of hydrogen and alkylgroups having from 1 to 2 carbon atoms, and most preferably R₂ and R₃are hydrogen. Preferred water-soluble nucleophiles may be selected fromthe group consisting of alkali hydroxides and alkaline earth hydroxides.More preferred water-soluble nucleophiles may be selected from the groupconsisting of lithium hydroxide, sodium hydroxide, and potassiumhydroxide. Preferably, Y is hydroxy.

In a second embodiment, the invention is directed to a method forpreparing a compound having Formula (I) which comprises contacting acompound having Formula (II) with an organic solvent-solublenucleophile, N², containing moiety Y, in an inert polar organic solvent.

In this second embodiment, the compound having Formula (I) may be:

The definition of X and R₁ are as defined above.

The organic solvent-soluble nucleophiles which may be employed in thepresent invention may be any organic solvent-soluble nucleophile whichis capable of selectively displacing the halogen group attached to thebenzylic position of the heterocyclic compound in an inert polar organicsolvent. The term “organic solvent-soluble nucleophile”, as used herein,refers to a nucleophile that can be dissolved in an organic solvent toyield a solution with a molarity equal to, or greater than, 0.01.Non-limiting illustrative organic solvent-soluble nucleophiles are thosethat contain a Y moiety, where Y may be selected from the groupconsisting of —OR₂, —NHR₂, —NR₂R₃, and —SR_(2.) R₂ and R₃ areindependently selected from the group consisting of hydrogen andbranched and unbranched alkyl and aryl groups having from 5 to 9 carbonatoms. Preferably, R₂ and R₃ are independently selected from the groupconsisting of hydrogen and branched and unbranched alkyl and aryl groupshaving from 5 to 8 carbon atoms, more preferably R₂ and R₃ areindependently selected from the group consisting of hydrogen andbranched and unbranched alkyl and aryl groups having from 5 to 7 carbonatoms, and most preferably R₂ and R₃ are hydrogen. Preferred organicsolvent-soluble nucleophiles may be selected from the group consistingof benzyltrimethyl ammonium hydroxide, tetrabutyl ammonium hydroxide,alkyl alcohols, aryl alcohols, alkylamines, arylamines, alkyl sulfides,aryl sulfides, and the salts thereof. More preferred organicsolvent-soluble nucleophiles are benzyltrimethyl ammonium hydroxide andtetrabutyl ammonium hydroxide. Preferably, Y is hydroxy.

The inert polar organic solvents which may be employed in the presentinvention may be any inert polar organic solvent which is capable ofdissolving the organic solvent-soluble nucleophile and the 5- or6-halomethyl quinoxaline thereby permitting the selective displacementof the halogen group attached to the benzylic position of theheterocyclic compound. The term “inert polar organic solvent”, as usedherein, refers to an organic solvent that does not react with theorganic solvent-soluble nucleophile or the 5- or 6-halomethylquinoxaline and promotes a reaction between the organic solvent-solublenucleophile and the 5- or 6-halomethyl quinoxaline. Non-limitingillustrative inert polar organic solvents may be selected from the groupconsisting of tetrahydrofuran, dioxane, 2-methoxyethyl ether,triethylene glycol dimethyl ether, dimethylsulfoxide (DMSO),methyl-tert-butyl ether (MTBE), and diethyl ether. Preferred inert polarorganic solvents may be selected from the group consisting oftetrahydrofuran, dioxane, 2-methoxyethyl ether, triethylene glycoldimethyl ether, and dimethylsulfoxide. More preferred inert polarorganic solvents may be selected from the group consisting oftetrahydrofuran, dioxane, and 2-methoxyethyl ether. Most preferred inertpolar organic solvents are tetrahydrofuran and dioxane.

In a third embodiment, the invention is directed to a method forpreparing a compound having Formula (I) which comprises contacting acompound having Formula (II) in an organic solvent with an aqueoussolution of a water-soluble nucleophile, N¹, containing moiety Y, in thepresence of a phase transfer catalyst.

In this third embodiment, the compound having Formula (I) may be:

The definition of X, R₁, and the water-soluble nucleophile are asdefined above.

The organic solvents which may be employed in the present invention maybe any organic solvent which is capable of dissolving the water-solublenucleophile and the 5- or 6-halomethyl quinoxaline with the assistanceof the phase transfer catalyst thereby permitting the selectivedisplacement of the halogen group attached to the benzylic position ofthe heterocyclic compound. Non-limiting illustrative organic solventsmay be selected from the group consisting of chlorobenzene,dichlorobenzenes, trichlorobenzenes, α,α,α-trichlorotoluene,fluorobenzene, difluorobenzenes, trifluorobenzenes, andα,α,α-trifluorortoluene. Preferred organic solvents may be selected fromthe group consisting of chlorobenzene, dichlorobenzenes, fluorobenzene,and difluorobenzenes. More preferred organic solvents are chlorobenzeneand dichlorobenzenes. The most preferred organic solvent ischlorobenzene.

The phase transfer catalysts which may be employed in the presentinvention may be any phase transfer catalyst which is capable ofdissolving the water-soluble nucleophile and the 5- or 6-halomethylquinoxaline in the organic phase thereby permitting the selectivedisplacement of the halogen group attached to the benzylic position ofthe heterocyclic compound. The phase transfer catalyst is typically anorganic salt (for example, tetraalkyl-ammonium salts,benzyltrimethylammonium salts, etc) that is soluble in both the aqueousphase and the organic phase. Non-limiting illustrative phase transfercatalysts may be selected from the group consisting oftetra-n-butyl-ammonium chloride, benzyltrimethylammonium chloride,benzyltrimethylammonium hydroxide, tetralkyl ammonium salts, tetraalkylsulfonium salts, and cetyltrimethylammonium salts.

The 5- and 6-halomethyl quinoxalines and the nucleophiles may be reactedin relative amounts ranging from about 1:1 to about 1:100, andpreferably from about 1:10 to about 1:30, respectively. The 5- and6-halomethyl quinoxalines and the nucleophiles may be reacted attemperatures ranging from about 25° C. to about 150° C., preferably fromabout 25° C. to about 100° C., and at pressures ranging from ambient toabout 100 psig, and preferably ambient.

The present invention is further illustrated by the following exampleswhich are presented for purposes of demonstrating, but not limiting, thepreparation of the compounds and compositions of this invention.

EXAMPLES Synthesis of methyl-quinoxaline from OTD (ortho-toluenediamine)

To a solution of 122 g of ortho-toluenediamine (1.0 mole) dissolved in500 cc of 2 M acetic acid, 250 cc of 4 M sodium acetate solution wasadded with stirring. The mixture was heated up to 60° C. and pouredrapidly into a solution of 298.4 g (1.05 moles) of sodium glyoxalbisulfite in 1500 cc of water previously heated to 60° C. The resultingdark solution was stirred for one hour and it was then cooled down in anice bath until the temperature had dropped below 10° C. The solution wasthen neutralized with 120 g of sodium hydroxide pellets. After thesodium hydroxide had dissolved, 500 g of potassium carbonate was added.During the addition of alkali, the solution turned red and a black oilseparated out. Most of the oily amine was removed by extraction withpentane or hexane and the combined organic phase was dried over MgSO₄,filtered and vacuum dried to give a brown oil that upon distillationgave methyl-quinoxaline (92 g) as a clear pale yellow to colorlessliquid (80% yield).

Example 2 Preparation of a Chlorobenzene Solution of6-bromomethyl-quinoxaline

In a 50 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolvedtogether with N-bromosuccinimide (2.32 g, 13.0 mmol) andbenzoyl-peroxide (0.15 g, 0.62 mmol) in 31 g of chlorobenzene. Thesolution was stirred with heating at 85° C. for 2.0 hours to yield areddish solution. The molar concentrations are shown in the followingtable:

Solvent [6QX] [NBS] [BP] ClPh 0.31 0.46 2.2 × 10⁻²

Analysis of the reddish solution by GC-MS showed mostly the formation ofcompounds 1 while compound 2 (ring bromination) was not detected:

Reaction Time = 120 min Product % Selectivity % Conversion 1 97.0 95.0Unknowns 3.0 2.5

The light reddish solution of 6-bromomethyl-quinoxaline was used toprepare 6-hydroxymethyl-quinoxaline as shown in the examples below.

Example 3 Preparation of a Solid Sample of 6-bromomethyl-quinoxaline

In a 100 ml flask, 6-methyl-quinoxaline (2.5 g, 17.4 mmol) was dissolvedtogether with N-bromosuccinimide (4.63 g, 19 mmol) and benzoyl peroxide(0.3 g, 1.24 mmol) in 70 g of 1,2-dichloroethane. The solution wasrefluxed for 150 minutes and analyzed. The concentrations of thereactants and some of their molar ratios are shown below:

Solvent [6QX] [NBS] [BP] [NBS]/{6QX] [6QX]/[BP] 1,2-DCE 0.31 0.46 0.0221.5 14

Total Reaction Time = 150 min Product % Selectivity % Conversion 1 93.485.0 2 1.6 1.5 3 5.0 4.6

The solution was cooled in the freezer overnight and the solid residuewas separated by filtration. The solid was washed with pentane and thewashings were combined with the liquid fraction. The clear reddishsolution was then vacuum dried to give an orange solid that was used inthe preparation of 6-hydroxymethyl-quinoxaline.

Example 4 Reflux of a Chlorobenzene Solution of6-bromomethyl-quinoxaline with an Aqueous Solution of Sodium Hydroxide.

A sample of solution of 6-bromomethyl-quinoxaline in chlorobenzeneprepared in Example 2 (3.90 g of solution) was mixed with 4 ml of 1.9 Maqueous sodium hydroxide and the two-phase liquid was refluxed for 30minutes. The chlorobenzene phase was analyzed by gas chromatography andmass spectroscopy. Most of the 6-bromomethyl-quinoxaline remainedunreacted. Careful GC-MS analysis of the organic phase showed thepresence of traces of 6-hydroxymethyl-quinoxaline. Although the presenceof a base was expected to react with the bromo-compound to yield6-hydroxymethyl-quinoxaline, reflux of the two phase mixture(water/chlorobenzene) was inappropriate for the reagents to get mixedyielding only a trace of the desired product.

Example 4 shows that mixing a chlorobenzene solution of6-bromomethyl-quinoxaline with an aqueous alkali hydroxide solution isnot an efficient method because of the unfavorable partition coefficientof the base in the organic phase.

Example 5 Reflux of a Chlorobenzene Solution of6-bromomethyl-quinoxaline with an Aqueous Solution of Sodium Hydroxidein the Presence of a Phase-Transfer Catalyst

In a 50 ml flask, the solution of 6-bromomethyl-quinoxaline inchlorobenzene prepared in Example 2 (24.1 g of solution) was mixed withan aqueous solution of sodium hydroxide prepared by dissolving 1.7 g ofsodium hydroxide in 4 ml of water. A phase-transfer catalyst(tetra-n-butyl-ammonium chloride) was added to the two-phase liquidmixture (0.1 g) followed by a gentle reflux. Upon heating, the reddishchlorobenzene solution turned dark-brown. The reaction was stopped after30 minutes refluxed and the aqueous phase was neutralized with a 4 Msolution of sulfuric acid. The chlorobenzene phase (reddish color) wasseparated and dried over anhydrous MgSO₄.

GC-MS analysis of the chlorobenzene phase showed absence of6-bromomethyl-quinoxaline and the presence of6-hydroxymethyl-quinoxaline. The chlorobenzene solution was evaporatedunder vacuum and the solid residue was washed with pentane to removesome remaining organic impurities. The brown solid residue (˜0.5 g, 52%yield)) was analyzed by GCMS showing mostly 6-hydroxymethyl-quinoxaline(80% purity).

Example 5 shows that in the presence of a phase transfer catalyst, thereaction can proceed with acceptable rates.

Example 6 Reflux of a Suspension of 6-bromomethyl-quinoxaline in AqueousSodium Hydroxide

The orange solid obtained in Example 3 was mixed with 50 ml of potassiumhydroxide (1.42 M). The reaction mixture was heated to reflux with theaid of a heating mantle for 20 minutes and analyzed. The aqueoussuspension was extracted with 250 ml of methylene chloride (5 times, 50ml each) and the extracts were dried over anhydrous MgSO₄, filtered andvacuum dried to give 1.5 g of a brownish solid (65% yield) composed of80% 6-hydroxymethyl-quinoxaline.

Upon heating, the 6-bromomethyl-quinoxaline melts and strong stirring isrequired to get the organic phase in contact with the alkali. Whenheating, the organic phase slowly turned brown particularly in the areaswhere the flask was in contact with the heating mantle. Example 6 showsthat some of the compound decomposed during heating and consequently amilder heating source may be used.

Example 7 Direct Reaction Between Solid 6-bromomethyl-quinoxaline andAqueous Base

A sample of 6-bromomethyl-quinoxaline (1.0 g) was placed in a 50 mlflask and 14.0 g of absolution of KOH (prepared by dissolving 4 g of KOHpellets in 20 g of water) was added. The yellowish suspension was heatedin a water bath to 80° C. and maintained at that temperature for about30 minutes. The aqueous solution was then neutralized with diluteaqueous sulfuric acid and the organic product was extracted with 150 mlof chloroform. The extracts were dried over anhydrous magnesium sulfate,filtered and vacuum dried to give a dark yellow solid (1.0 g) that waswashed with pentane and ether to give 0.6 g (˜80% yield) of a yellowsolid mostly composed of 6-hydroxymethyl-quinoxaline.

Example 7 shows that when a water bath at 80° C. is used as a heatingsource, the organic phase does not turned completely brown but darkyellow. The addition of a phase transfer catalyst minimized even morethe formation of brown products (tars) resulting from the thermaldecomposition of 6-bromomethyl-quinoxaline. Thus, minimizing heating andfinding a solvent media that favors the solution of both6-bromomethyl-quinoxaline and the base seems to be the most appropriateprocedure to make 6-hydroxymethyl-quinoxaline from its bromo compound.

Example 8 Synthesis of 6-hydroxymethyl-quinoxaline from6-bromomethyl-quinoxaline and benzyltrimethyl-ammonium Hydroxide

In a 50 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolvedtogether with N-bromosuccinimide (2.32 g, 13.0 mmol) and benzoylperoxide (0.15 g, 0.62 mmol) in 31 g of chlorobenzene. The solution wasstirred with heating at 85° C. for 2.0 hours to yield a reddishsolution. The solution was cooled down to room temperature and onevolume of pentane was added to facilitate the precipitation ofsuccinimides. The solid was filtered (1.6 g), washed with pentane andthe extracts were combined with the chlorobenzene solution. Thissolution was then vacuum dried to give a yellow solid mainly composed of6-bromomethyl-quinoxaline (1.92 g). This solid was dissolved in 38 g ofTHF and mixed with 4.24 g of a 40% commercial aqueous solution ofbenzyltrimethyl ammonium hydroxide. Samples were analyzed during thecourse of the reaction showing a progressive conversion of6-bromomethyl-quinoxaline into the hydroxy derivative. The pale yellowsolution was stirred at room temperature overnight until the reactionwas completed and no other by-products were detected by GCMS analysis.The alkaline solution was neutralized with dilute sulfuric acid (1 M)and pH adjusted with sodium bicarbonate. The solution was vacuum driedto give a yellow residue (2.5 g) that was dissolved in methylenechloride and extracted with water to remove the organic salt. Themethylene chloride solutions were dried over anhydrous MgSO₄ and thesolution evaporated to give a pale yellow solid mostly composed of6-hydroxymethyl-quinoxaline (1.15 g, ˜83% yield).

Example 8 shows that the use of a phase transfer reagent minimizesdecomposition of 6-bromomethyl-quinoxaline (no tars) because heating isnot required to improve the miscibility of the phases.

Example 9 Analytical Data of 6-hydroxymethyl-quinoxaline

A sample of the brownish solid obtained in Example 6 was furtherpurified by distillation. The product was isolated as a white solid thatshowed the following analytical data: MS (70 ev): 160 (M⁺); 143 (M⁺—OH);131 (M⁺—OH—C); ¹H NMR (CDCl₃): 4.85 (s, 2H, ═CH₂), 5.2 (br, 1H, —OH),7.65 (d, 1H, C—H aromatic), 7.90 (d, 1H, C—H aromatic), 7.95 (s, 1H, C—Haromatic), 8.65 (s, 2H, C—H aromatic).

Example 10 Synthesis of 6-n-butylaminomethyl-quinoxaline

In a 50 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolvedtogether with N-bromosuccinimide (2.32 g, 13.0 mmol) andbenzoyl-peroxide (0.15 g, 0.62 mmol) in 31. g of chlorobenzene. Thesolution was stirred with heating at 85° C. for 2.0 hours to yield areddish solution. The solution was cooled down to room temperature andone volume of pentane was added to facilitate the removal ofsuccinimides. The precipitate was washed with pentane and the extractswere combined with the chlorobenzene solution. The yellow solution wasvacuum dried to give a yellow residue mainly composed of6-bromomethyl-quinoxaline. The yellow solid was dissolved in 19.0 g ofn-butylamine to give a yellow solution that was stirred at roomtemperature for ˜5 minutes. Analysis of a sample showed that the6-bromomethyl-quinoxaline was consumed to give exclusively6-n-butylaminomethyl-quinoxaline as a deep yellow oil (1.71 g, 92% overall yield). MS (70 ev): 215 M⁺, 172 (M⁺—CH₃—CH₂—CH₂),143(M⁺—CH₃—CH₂—CH₂—CH₂).

Example 10 shows that some organic solvent-soluble nucleophiles(alkylamines, for example) can readily react with6-bromomethyl-quinoxaline because the compound is completely soluble inthe organic phase. Example 10 shows that 6-bromomethyl-quinoxalinecompletely reacted with n-butylamine in few minutes at room temperatureto give 6-n-butylaminomethyl-quinoxaline. In this example, n-butylamineacted as both the nucleophile and the solvent.

Throughout this application, various publications have been referenced.The disclosures in these publications are incorporated herein byreference in order to more fully describe the state of the art.

1. a) G. W. H. Cheeseman in “Advances in Heterocyclic Chemistry” by A.R. Katritzky Academic Press. Vol. 2. pp. 203-221. 1963. b) G. W. H.Cheeseman and E. S. G. Werstiuk 367-419 in “Advances in HeterocyclicChemistry” by A. R. Katritzky Academic Press. Vol. 22. pp. 203-221. 1978c) J. C. Cavagnol, F. Y. Wiselogle, J. Am. Chem. Soc., 69, 795, 1947.

2. O. Gawron, P. E. Spoerri, J. Am. Chem. Soc., 67, 514, 1945.

3. R. Mizzoni, P. E. Spoerri, J. Am. Chem. Soc., 67, 1652, 1945.

4. O. Gawron, A. Rampal, P. Johnson, J. Am. Chem. Soc., 94, 5396, 1972.

5. R. C. DeSelms, R. J. Greaves, W. R. Schleigh, J. Heterocyclic Chem.,11, 595, 1974.

6. Venet et al. U.S. Pat. No. 5,028,606 (1991).

7. (a) R. Granger, S. Deadwyler, M. Davis, B. Moskovitz, M. Kessler, G.Rogers, G. Lynch, Synapse, 22, pp. 332-337, 1996. (b) G. Lynch, M.Kessler, G. Rogers, J. Ambross-Ingerson, R. Granger, R. S. Schehr,International Clinical Psycopharmacology, 11, pp.13-19, 1996.

8. 2,3-Pyrazinedicarboxylic acid: “Organic Synthesis” Coll. Vol. 4 pp.824-827, J. Wiley & Sons, Inc. NY., 1963.

9. D. F. Gavin, U.S. Pat. No. 3,960,963 (1976).

While a number of embodiments of this invention have been represented,it is apparent that the basic construction can be altered to provideother embodiments which utilize the invention without departing from thespirit and scope of the invention. All such modifications and variationsare intended to be included within the scope of the invention as definedin the appended claims rather than the specific embodiments which havebeen presented by way of example.

What is claimed is:
 1. A method for preparing a compound having Formula(I):

which comprises contacting a compound having Formula (II) with anorganic solvent water-soluble nucleophile, N², containing moiety Y, inan inert polar organic solvent; wherein X is chloro or bromo; R₁ isselected from the group consisting of hydrogen and branched andunbranched alkyl and aryl groups having from 1 to 9 carbon atoms; and Yis hydroxy.
 2. The method according to claim 1, wherein the compoundhaving Formula (I) is:


3. The method according to claim 1, wherein the compound having Formula(I) is:


4. The method according to claim 1, wherein X is chloro.
 5. The methodaccording to claim 1, wherein X is bromo.
 6. The method according toclaim 1, wherein R₁ is selected from the group consisting of hydrogenand branched and unbranched alkyl and aryl groups having from 1 to 6carbon atoms.
 7. The method according to claim 1, wherein the organicsolvent-soluble nucleophile, N², is selected from the group consistingof benzyltrimethly ammonium hydroxide and tetrabutyl ammonium hydroxide.8. The method according to claim 1, wherein the inert polar organicsolvent is selected from the group consisting of tetrahydrofuran,dioxane, 2-methoxyethyl ether, triethylene glycol dimethyl ether,dimethylsulfoxide, methyl-tert-butyl ether, and diethyl ether.